Real-world safety of ulinastatin: a post-marketing surveillance of 11,252 patients in China

Background The safety assessment of ulinastatin can guide clinical practice. The present study aimed to investigate the real-world safety of ulinastatin in China. Methods This multicenter study retrospectively analyzed the post-marketing surveillance data of consecutive patients treated with ulinastatin between August 2014 and June 2017 in the general wards and the intensive care units (ICU) of nine hospitals in China. Adverse drug reactions/adverse drug events (ADRs/ADEs) were collected and evaluated in a post-marketing database. Results A total of 11,252 consecutive patients were included in the study: 7009 ICU patients and 4243 general ward patients. Eleven patients with ADRs/ADEs were observed, including nine ICU patients and two general ward patients. The clinical manifestations were liver dysfunction (n = 5 ICU cases, n = 1 general case), thrombocytopenia (n = 2 ICU cases, n = 1 general case), leukopenia (n = 1 ICU case), and rash (n = 1 ICU case). During the study period, the drug ADR/ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). Among the 11,252 valid patients, only 327 received ulinastatin in accordance with the drug specifications. After excluding unreasonable drug use, the calculated ADR rate was 3.06‰ (1/327 × 1000‰) (95% confidence interval: 0.0‰-17.1‰). In ICU and general ward patients, the use of other drugs combined with ulinastatin was associated with the occurrence of ADRs/ADEs (100% with ADRs/ADEs vs. 0% in controls, P < 0.001). Conclusions The incidence of ADRs/ADEs of ulinastatin is < 5‰. The ADRs/ADEs involved limited organs, mainly the skin, gastrointestinal tract, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the focus of surveillance. Supplementary Information The online version contains supplementary material available at 10.1186/s40360-022-00585-3.

Clinical trials showed that the adverse drug events (ADEs) of ulinastatin include dizziness, injection site pain, decreasing white blood cell (WBC), nausea, vomiting, allergic dermatitis, phlebitis, and rhinorrhea [13][14][15][16][17][18]. Still, some clinical trials did not report the safety of ulinastatin [12,19] or analyze the adverse effects [4,10]. In addition, the clinical trials usually select the cases and cannot represent the actual situation [8,20,21]. Hence, the post-marketing safety reevaluation of ulinastatin for injection would be helpful for the guidance of clinical use.
This multicenter study aimed to investigate the safety of ulinastatin and analyzed the data from a post-marketing database about the clinical use and safety of ulinastatin in China. A large-scale investigation on its safety might assist the policy formulation and implementation of the administration department and guide the rational use.

Study design and data source
This multicenter study retrospectively analyzed the post-marketing data of patients who received ulinastatin (Guangdong Techpool Bio-pharma Co., Ltd., Guangdong, China) between August 2014 and June 2017 in general wards and intensive care units (ICUs) of nine hospitals in China.
The study protocol was approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine (No. B2014-056-01) as the lead center. The study was carried out in accordance with the relevant guidelines and regulations ("Opinions on Reforming the Review and Approval System for Drugs and Medical Devices" in 2015 by the CFDA and "Regulations for the Implementation of the Drug Administration Law of the People's Republic of China" in 2016 by the State Council). The clinical data were from nine hospitals. The requirement for informed consent was waived by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine.

Routine assessments
The use of ulinastatin for injection, such as indications, routes, dosage, solvents, duration, concentration, and course, were evaluated as package inserts. According to the package insert, for acute pancreatitis and chronic recurrent pancreatitis, in the initial stage, 100,000 U are dissolved in 500 mL of 5% glucose injection or 0.9% sodium chloride injection for intravenous drip, administered 1-3 times/day, 1-2 h apart, and reducing the dose as the symptoms disappear. For acute circulatory failure, 100,000 U are dissolved in 500 mL of 5% glucose injection or 0.9% sodium chloride injection for intravenous drip pr in 5-10 mL of 0.9% sodium chloride injection slowly, 1-3 times/day, 1-2 h apart. The doses can be appropriately increased or decreased according to age and symptoms. In China, all off-label uses only need to be authorized by the director of the clinical department rather than by the pharmaceutical therapy and safety committee of the hospital.
The ATC coding was used for the drugs, and the ICD10 codes were used for the diseases. Only safety events related to the rational use of ulinastatin were ADRs according to the package inserts, and safety events related to the off-label use of ulinastatin were ADEs. The pharmacists investigated patients' information, medication treatment, and ADRs and filled in the case report forms (CRFs). All ADEs were identified by the physicians and reviewed by experts to confirm their relevance to ulinastatin. ADRs/ADEs were assessed following the Common Adverse Event Evaluation Standard 4.0 (CTCAE 4.0).

Statistical analysis
All data were processed using SPSS 18 (SPSS Inc. Released 2009. PASW Statistics for Windows. Chicago: SPSS Inc. USA). The continuous data were presented as means ± standard deviation and evaluated using the independent samples t-test. Categorical data were presented as n (%) and evaluated using the chi-square test. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) of the risk factors. Two-sided P < 0.05 was statistically significant.
The ADR/ADE cases were matched with non-ADR/ ADE cases in a 1:4 ratio and according to clinical departments, diagnosis, sex, and age.

Drug combination
Combined drugs were used in 1715 ICU cases, with 2015 times. The mixed drugs mainly include troxerutin injection, sodium phosphocreatine for injection, and sodium monosialate tetrahexosaccharide ganglioside. There were 38 combined drugs. A total of 28 ICU cases were filled in the CRFs with 272 combined medication events. Cardiovascular drugs were the most used, with 55 (20.22%), followed by digestive and electrolytes and nutrition drugs with 43 and 39 (15.81 and 14.34%), respectively. The main drugs were 5% glucose, dopamine, and ambroxol injection.
In the general ward cases, other drugs were used in 24 cases, with 43 times. There were 14 mixed drugs, including insulin, magnesium isoxalate, and reduced glutathione. There were 243 cases with combined drug use, for 301 times. Among them, the electrolytes and nutritional drugs were the most common, with 64 cases (21.26%), followed by anesthetic and digestive drugs with 39 and 27 (12.95 and 8.97%), respectively. The main drugs were 0.9% sodium chloride injection, ambroxol, propofol, and omeprazole.

Adverse drug reactions
In this study, 11 cases of ADR/ADE were observed, including nine ICU cases and two general cases. The clinical manifestations were abnormal liver function (3 ICU cases and 1 general case), liver function damage (1 ICU case), thrombocytosis (1 ICU case and 1 general case), thrombocytopenia (1 ICU case), leukocytosis (1 ICU case), rash (1 ICU case), and leukopenia (1 ICU case) ( Table 3). Systems involved skin and accessory lesions, digestive system, and blood system. One case was evaluated as "probably relevant" and 10 as "possibly relevant". The severity of ADRs/ADEs was graded grade 1-2 in 10 cases and grade 4 in 2 ( Table 4). ADRs/ADEs occurred within 6 days after administration. After ADRs/ ADEs, all cases stopped ulinastatin. Only one case of rash was treated with calamine lotion. All cases recovered or improved within 11 days after the occurrence of ADRs/ ADEs without the reuse of ulinastatin again ( Table 4).
The drugs used by the patients who experienced ADR/ ADEs are shown in Supplementary Tables S1 and S2. Among the nine patients with ADR/ADEs in the ICU, a total of 100 combined drugs were used; the most common were electrolyte, acid-base balance, and nutritional drugs, followed by digestive system drugs, antimicrobial drugs, cardiovascular system drugs, and respiratory system drugs (Supplementary Table S2). Two general ward patients received 36 combined drugs. The most common were anesthetics, followed by cardiovascular system drugs, hematological system drugs, endocrine system drugs, and antimicrobial drugs (Supplementary Table  S3).

Univariable analyses after matching
In the ICU, 45 cases were analyzed in the univariable analyses after matching, including 9 cases with evaluated Table 3 Safety of ulinastatin in clinical practice ADRs/ADEs (case group) and 36 without (control group). The case group was 54.58 ± 23.02 years old, and the control group was 55.13 ± 22.08 years old (P = 0.977). Only the combined drugs were statistically significant between the two groups (P = 0.001) ( Table 5). A total of 100 combined drug use were observed in the case group, while the control group had no combined drug use. Electrolyte and nutritional drugs were the most common, with 21 cases, followed by digestive drugs and antibiotics, with 19 and 12 cases, respectively. Among the general ward cases, 10 cases were analyzed in the univariable analyses after matching, including two cases with ADRs/ADEs (case group) and eight cases without (control group). The age of the case group was 59.23 ± 2.66 years old, and the controls were 59.60 ± 2.30 years old. There were no obvious differences between the two groups regarding the history of infectious diseases and trauma surgery (all P > 0.05). Age, sex, food, and drug allergy history, and allergy history could not be evaluated. There was a difference (P = 0.002) between the two groups regarding combined drugs (Table 6). There were 36 combined drug uses in the case group, while the control group had not. Anesthesia drugs were used eight times, followed by cardiovascular and blood drugs (7 and 6 times, respectively).

Adverse drug reaction rate
In the study, the ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). However, the ADR cases group did not include unreasonable drug use. In the study, only 327 patients received ulinastatin according to package inserts, and excluding the cases of unreasonable drug use, the ADR rate of ulinastatin for injection was 3.06‰ (1/327 × 1000‰), and the 95% CI was 0.00‰-17.10‰.

Discussion
Ulinastatin is generally well-tolerated and has few ADEs in clinical trials, but real-world evidence (RWE) of safety was lacking. Therefore, this multicenter post-marketing surveillance study aimed to investigate the real-world safety of ulinastatin in China. The RWE results suggest that the incidence of ulinastatin ADR/ADE is < 5‰. The ADRs/ADEs involve limited sites, mainly the skin, digestive system, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the important target of surveillance. RWE is important to the safety monitoring of drugs. Indeed, RWE studies examine the actual patients who receive the drug in opposition to clinical trials, in which highly selected patients are treated with the drug. In clinical trials, patients with comorbidities and confounding factors are usually excluded from determining the exact effects of the drug, but such patients will receive the drug in actual  Excluding unreasonable drug use, ADR/ADE rate was 3.06‰ (1/327 × 1000‰), which was "occasional" according to the ADR/ADE classification standard. It is lower than the seven ADR/ADE cases among 497 cases (1.41%) in the meta-analysis by Chen et al. [18]. However, the meta-analysis only included randomized controlled trials of ulinastatin vs. traditional Chinese medicine combined with ulinastatin.
The ADRs/ADEs in the RWE study involved skin and accessory damage, digestive, and blood system. 1 case of ADR/ADE was moderate, 1 case was life-threatening, and the other 8 cases were mild. All cases were alleviated or recovered 11 days after drugs' were discontinued without intervention. Therefore, using ulinastatin is safe, and ADR/ADE is rare. The above RWE data help identify methods, characteristics and focuses of safety monitoring of drug usage.
As the rate of ADRs/ADEs might vary with the geographical distribution, population, living environment, and habits of the patients, it is necessary to conduct a nationwide investigation on a large scale. More than 10,000 cases were included in the study, but some very rare ADRs/ADEs might have been missed. Therefore, it is suggested that within the allowed limits of the human and financial resources, the total sample size should be expanded to > 100,000 cases. Data collection is still ongoing.
Most of the ADRs/ADEs occurred on the first day of medication, suggesting that the patients should be particularly closely observed on the first day of medication, especially during the first 30 min after infusion, and stay alert to the occurrence of ADRs/ADEs to be able to react promptly by stopping or reducing the dosage. Still, in this study, ADR/ADE occurred within 6 days after medication, suggesting that clinical attention should be paid during hospitalization since ADRs/ADEs can still be observed after ulinastatin administration.
In addition to the ADRs/ADEs, this study characterized the use of ulinastatin in nine hospitals in China. The results revealed that most of the cases (97.10%) did not receive ulinastatin according to the product monograph. The type and dose of solvent and the number of uses per day were off-label in most cases. It is supported by a previous retrospective study in China that showed that the dosage was inconsistent with the recommendations in many cases [26]. Nevertheless, even when including the off-label use of ulinastatin, the rate of ADR/ADE was still low. Still, surveillance should be performed by the pharmacy departments to ensure that the drug is used according to the recommendations. It constitutes the basis for the rationale and safe use of drugs in hospitals. The recommended solvents for ulinastatin are saline or glucose solutions, with a volume of 500 ml for infusion, 5-10 ml of solvent during intravenous injection, and 5-10 ml of solvent for an intravenous pump. The maximal dosing per day should not exceed three times, and the dose should be 100,000-200,000 U.
This study has some limitations. Despite its large sample size, the actual rate of ADRs/ADEs was low, probably preventing the observation of rare ADRs/ADEs. In addition, because of the low occurrence of ADRs/ADEs, the logistic regression results should be taken with caution. Secondly, about two-thirds of the patients were from the ICU and were with severe conditions that might have hidden some mild ADRs/ADEs, resulting in an underestimation of the ADR/ADE rate. The analyzable data was limited. Finally, ulinastatin is only approved in China, India, South Korea, and Japan, limiting the scope of the present study.

Conclusions
In conclusion, the RWE ADR/ADE rate of ulinastatin is < 5‰. ADR/ADEs are observed in cases of ulinastatin combined with other drugs. The ADRs/ADEs included liver dysfunction, thrombocytopenia, leukopenia, and rash. In most cases, the ADR/ADEs gradually resolved after discontinuing the drug. This RWE study revealed inappropriate/off-label uses of ulinastatin for most patients. We should focus on monitoring and education during the use of ulinastatin.